Limits...
A pentacyclic triterpene natural product, ursolic acid and its prodrug US597 inhibit targets within cell adhesion pathway and prevent cancer metastasis.

Xiang L, Chi T, Tang Q, Yang X, Ou M, Chen X, Yu X, Chen J, Ho RJ, Shao J, Jia L - Oncotarget (2015)

Bottom Line: Immunohistochemical analysis revealed that US597 treatment regulates ICAM-1, a biomarker of metastasis.We did not detect side effects with US597 in mice such as weight loss, viscera tissues toxicity and blood cell abnormalities.Thus, UA and US597 are potential drug candidates for preventing cancer metastasis.

View Article: PubMed Central - PubMed

Affiliation: Cancer Metastasis Alert and Prevention Center and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou 350002, China.

ABSTRACT
Here we showed that ursolic acid (UA), a pentacyclic triterpene natural product, and its novel prodrug derivative US597 suppressed cancer cells adhesion, invasion and migration. This effect was accompanied by inhibition of focal adhesion signaling pathway including alterations in ICAM-1, VCAM-1, E-selectin, P-selectin, integrin α6β1, FAK, Src, paxillin and PTEN. While oral administration of UA or US597 increases survival rate of melanoma lung metastasis in C57BL/6 mice, US597 treatment extend the survival rate above that of UA. Immunohistochemical analysis revealed that US597 treatment regulates ICAM-1, a biomarker of metastasis. We did not detect side effects with US597 in mice such as weight loss, viscera tissues toxicity and blood cell abnormalities. Thus, UA and US597 are potential drug candidates for preventing cancer metastasis. Molecular and cellular study data suggest that UA and US597 modulate expression of cell adhesion molecules within focal adhesion signaling pathway leading to cancer cell motility.

No MeSH data available.


Related in: MedlinePlus

A possible mechanism underlying the inhibitory effect of UA/US597 on cancer metastasis
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4496218&req=5

Figure 9: A possible mechanism underlying the inhibitory effect of UA/US597 on cancer metastasis

Mentions: Tumor invasion and metastasis involve multiple processes, which depend on specific cell-to-cell and cell-to-ECM (extracellular matrix) interactions. These events are mediated in part by integrins that act as receptors for ECM proteins [31]. Integrins are cell-surface glycoprotein receptors that consist of alpha and beta subunits. During cancer metastasis, the expression levels of many different integrins are up-regulated, such as α1β1, α2β1, α3β1, α5β1 and α6β1 [10–12, 32, 33]. Among these, the integrin α6β1, a receptor for laminins, is thought to exclusively bind laminin and to mediate adhesion of human hepatocellular carcinoma cells on substrata coated with this protein [11, 12]. There are reports showing that blocking the expression and activity of integrin α6β1 and its downstream signaling regulator can significantly inhibit hepatocellular carcinoma metastasis [34], which may be related with the inhibition of tumor adhesion, migration, and invasion. In our microarray results, we found 720 genes were altered after US597 treatment (Supplementary Figure S2). Some selected genes were categorized according to their known function. Among them, 13 genes were associated with the focal adhesion, including FAK and PTEN (Figure 4A). We investigated the expression of ITGA6, ITGB1, FAK and PTEN mRNA after UA/US597 treatment of HepG2 cells by qRT-PCR (Figure 4B). In addition, structural docking presents a possible binding mode of UA in the FAK active site (Figure 4C and 4D). In this study, we also examined the inhibition effects of UA/US597 on the expression of integrins (α6β1) and downstream FAK, Src, paxillin and up-regulates PTEN on the surface of HepG2 cells (Figure 5). UA/US597 is able to modulate the expression of proteins linked to proliferation, adhesion, invasion and migration in HepG2 cells (Figure 9). Taken together, our data suggested that the anti-metastatic effect of UA/US597 may be mediated by suppressing the integrin α6β1 and its downstream signaling regulator expression on the cancer cell surface.


A pentacyclic triterpene natural product, ursolic acid and its prodrug US597 inhibit targets within cell adhesion pathway and prevent cancer metastasis.

Xiang L, Chi T, Tang Q, Yang X, Ou M, Chen X, Yu X, Chen J, Ho RJ, Shao J, Jia L - Oncotarget (2015)

A possible mechanism underlying the inhibitory effect of UA/US597 on cancer metastasis
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496218&req=5

Figure 9: A possible mechanism underlying the inhibitory effect of UA/US597 on cancer metastasis
Mentions: Tumor invasion and metastasis involve multiple processes, which depend on specific cell-to-cell and cell-to-ECM (extracellular matrix) interactions. These events are mediated in part by integrins that act as receptors for ECM proteins [31]. Integrins are cell-surface glycoprotein receptors that consist of alpha and beta subunits. During cancer metastasis, the expression levels of many different integrins are up-regulated, such as α1β1, α2β1, α3β1, α5β1 and α6β1 [10–12, 32, 33]. Among these, the integrin α6β1, a receptor for laminins, is thought to exclusively bind laminin and to mediate adhesion of human hepatocellular carcinoma cells on substrata coated with this protein [11, 12]. There are reports showing that blocking the expression and activity of integrin α6β1 and its downstream signaling regulator can significantly inhibit hepatocellular carcinoma metastasis [34], which may be related with the inhibition of tumor adhesion, migration, and invasion. In our microarray results, we found 720 genes were altered after US597 treatment (Supplementary Figure S2). Some selected genes were categorized according to their known function. Among them, 13 genes were associated with the focal adhesion, including FAK and PTEN (Figure 4A). We investigated the expression of ITGA6, ITGB1, FAK and PTEN mRNA after UA/US597 treatment of HepG2 cells by qRT-PCR (Figure 4B). In addition, structural docking presents a possible binding mode of UA in the FAK active site (Figure 4C and 4D). In this study, we also examined the inhibition effects of UA/US597 on the expression of integrins (α6β1) and downstream FAK, Src, paxillin and up-regulates PTEN on the surface of HepG2 cells (Figure 5). UA/US597 is able to modulate the expression of proteins linked to proliferation, adhesion, invasion and migration in HepG2 cells (Figure 9). Taken together, our data suggested that the anti-metastatic effect of UA/US597 may be mediated by suppressing the integrin α6β1 and its downstream signaling regulator expression on the cancer cell surface.

Bottom Line: Immunohistochemical analysis revealed that US597 treatment regulates ICAM-1, a biomarker of metastasis.We did not detect side effects with US597 in mice such as weight loss, viscera tissues toxicity and blood cell abnormalities.Thus, UA and US597 are potential drug candidates for preventing cancer metastasis.

View Article: PubMed Central - PubMed

Affiliation: Cancer Metastasis Alert and Prevention Center and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou 350002, China.

ABSTRACT
Here we showed that ursolic acid (UA), a pentacyclic triterpene natural product, and its novel prodrug derivative US597 suppressed cancer cells adhesion, invasion and migration. This effect was accompanied by inhibition of focal adhesion signaling pathway including alterations in ICAM-1, VCAM-1, E-selectin, P-selectin, integrin α6β1, FAK, Src, paxillin and PTEN. While oral administration of UA or US597 increases survival rate of melanoma lung metastasis in C57BL/6 mice, US597 treatment extend the survival rate above that of UA. Immunohistochemical analysis revealed that US597 treatment regulates ICAM-1, a biomarker of metastasis. We did not detect side effects with US597 in mice such as weight loss, viscera tissues toxicity and blood cell abnormalities. Thus, UA and US597 are potential drug candidates for preventing cancer metastasis. Molecular and cellular study data suggest that UA and US597 modulate expression of cell adhesion molecules within focal adhesion signaling pathway leading to cancer cell motility.

No MeSH data available.


Related in: MedlinePlus